2012 AAN Meeting: DMD, BMD Briefs

Findings on the immune response to dystrophin in Duchenne and Becker MD, treatment of cardiomyopathy in DMD, and eteplirsen in DMD were presented

Article Highlights:

Presentations at the 2012 American Academy of Neurology meeting included the following findings:

The immune response to dystrophin should be taken into consideration in clinical trials in DMD and BMD; and, it can potentially be lessened by treatment with corticosteroids.

Treatment with either an ACE inhibitor or an ACE inhibitor plus a beta blocker was beneficial for DMD-related cardiomyopathy; a podcast on this topic became available in May 2012.

The exon-skipping drug eteplirsen was safe and resulted in production of enough dystrophin protein to potentially provide a functional benefit if treatment were to continue for a longer period of time.

Immune response to dystrophin probed

Some DMD patients mount an immune response to the dystrophin protein when it's supplied via gene therapy because of pre-existing immunity to this protein. This response is a limiting factor in therapy development for DMD.

But corticosteroids may help suppress this unwanted immune response, reported Kevin Flanigan from Nationwide Children's Hospital in Columbus, Ohio, citing results of a new study supported by the National Institutes of Health (NIH).

The study included 76 people with DMD, six with BMD and 21 healthy children who served as a control group. Twenty-four of the DMD patients were taking the corticosteroid drug prednisone, and 29 the similar corticosteroid deflazacort. Seventeen of the DMD patients were not taking a corticosteroid medication.

The investigators found that:

Immune system cells from 53 percent (nine out of 17) of the DMD patients who were not taking a corticosteroid reacted against the dystrophin protein when they were exposed to it.

By contrast, immune system cells from only 25 percent of DMD patients taking prednisone (six out of 24) and only 17 percent of those taking deflazacort (five out of 29) reacted against the dystrophin protein.

The immune cells from only one person with BMD (out of six tested) reacted against dystrophin.

Immune cells from the 21 healthy children (control group) did not react against dystrophin; neither did immune cells from an additional 30 adults from a previous study who also were considered a control group.

The researchers concluded that:

Corticosteroids appear to suppress dystrophin-specific immune system responses in DMD patients, and this action may be related to their benefits in DMD.

An immune response to dystrophin is not as common in BMD as it is in DMD and does not appear to occur at all in people who do not have either disease.

The immune response to dystrophin should be assessed prior to and throughout clinical trials in DMD or BMD, since it may influence trial outcomes.

Drugs help DMD-related cardiomyopathy

A multicenter study supported in part by MDA and conducted by the MDA DMD Clinical Research Network has found that treatment of cardiomyopathy (deterioration of the heart muscle) in DMD with an ACE inhibitor alone, or with an ACE inhibitor plus a beta blocker, resulted in better heart function than no treatment.

Heart function was assessed by a series of echocardiograms measuring changes in ejection fraction, the amount of blood pumped out with each cardiac cycle (heartbeat). A normal ejection fraction is at least 55 percent.

ACE (angiotensin converting enzyme) inhibitors help relax blood vessels, reducing the workload on the heart. Beta (beta adrenergic receptor) blockers cause the heart to beat more slowly and with less force.

The 45 patients in this study who had DMD-related cardiomyopathy received either the ACE inhibitor lisinopril alone, or lisinopril plus the beta blocker metoprolol. Only those participants whose average heart rates were greater than 100 beats per minute received the beta blocker.

Twenty-four of the trial participants also were studied prior to any treatment, so that "natural history" data on the progression of DMD-related cardiomyopathy could be obtained.

The investigators found that:

At the end of one year, the heart function of both treated groups had improved compared to the average function prior to treatment (natural history). There was no difference in outcome between those who received only lisinopril and those who received lisinopril plus metoprolol.

For those participants who were studied for an additional three years, heart function stabilized, although some required increases in drug dosages to maintain stabilized function.

Be sure to check out a May 2012 podcast provided by Nationwide Children's Hospital's "This Month in Muscular Dystrophy" in which pediatric cardiologist Hugh Allen, an investigator on the cardiomyopathy study, provides an in-depth discussion of the implications of the study.

At the AAN meeting, neurologist Jerry Mendell from Nationwide Children's Hospital in Columbus, Ohio, principal investigator on this study, offered a more detailed analysis of the findings. (MDA provided supplemental support from this trial through Mendell.) A poster presentation supplemented Mendell's talk.

New information presented at the AAN meeting included the following:

Eteplirsen was safe at a dosage of up to 50 milligrams per kilogram of body weight per week for 28 weeks; there were no treatment-related adverse events.

There was a trend toward slower progression of the disease, as measured by the distance walked in six minutes, if the two lowest-performing trial participants were removed from the 24-week analysis.

Eteplirsen induced dystrophin production in between 15 and 30 percent of sampled muscle fibers; this level of dystrophin is likely to produce functional benefits if maintained over time.

For more on the eteplirsen findings, see the information posted April 25 on the AVI BioPharma site under Events & Presentations.